NO865203L - SULFINYL AND SULPHONYL SUBSTITUTED 3-BENZAZEPINES. - Google Patents

Abstract

Compounds of the formula (1) : <CHEM> and pharmaceutically acceptable acid addition salts are described wherein R is hydrogen, or C1-C6alkyl or C3-C5alkenyl; R<1> is SOR<3>, SO2R<3> or SO2NR<4>R<5>; R<2> is hydrogen, C1-C6alkyl or R<6>O-; R<3> is C1-C6alkyl or trifluoromethyl; R<4> and R<5> are hydrogen or C1-C6alkyl; and R<6> is hydrogen, C1-C6alkyl or C1-C6alkanoyl, provided that when R<1> is SO2NH2, R<2> is R<6>O- or C1-C6alkyl. These compounds are useful in the treatment of gastrointestinal motility disorders. Pharmaceutical compositions and methods of use are described. Intermediates and processes for the preparation of compounds of the formula (1) are described.

Description

This invention relates to new sulfinyl- and sulfonyl-substituted benzazepine compounds, pharmaceutical compositions containing them and methods for treating gastric and intestinal motility disorders by administering these compounds.

The compounds in this invention are used in

treatment of stomach and intestinal disorders, especially stomach and intestinal motility disorders. The compounds are therapeutically useful for gastroesophageal reflux disease and disorders of delayed gastric emptying of various etiologies including diabetes, surgery and idiopathic delayed emptying. The compounds can also be used to treat disorders of upper GI motility, respiration, early satiety, anorexia nervosa and in diagnostic radiology or to facilitate incubation.

The compounds produced in this invention have the following formula (1):

where

R is hydrogen, C 1 -C 6 alkyl or C 3 -C 8 alkenyl;

R<1> is SOR<3>, SO2 R3 or SO2 NR4 R3 ;

R<2> is hydrogen, C1-C6 alkyl or R<6>O-;

R<3> is C 1 -C 6 alkyl or trifluoromethyl;

R<4> and R<3> are hydrogen or C1-C6 alkyl; and

R<6> is hydrogen, C1-C6-alkyl or C-C6-alkanoyl,

provided that when R<1> is SO2 NH2 , R<2>R6 is 0- or

C 1 -C 6 alkyl,

or a pharmaceutically acceptable acid addition salt thereof.

Special compounds with formula (1) are those where R<1> is in the 7-position. Other special compounds with formula (1) are those where R<1> is in the 7-position and R<2> is in the 8-position.

A group of compounds of formula (1) is that where R<1> is

SO2 R3 or SO2NR<4>R<9>, R<2> is hydrogen, alkoxy or hydroxy, R<3>

is methyl and R is hydrogen and in addition R<1> can be in the 7-position and R<2> can be in the 8-position.

Specific compounds prepared in this invention are: 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-hydroxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine. According to the present invention, a compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof is prepared by a) for the preparation of compounds of formula (1) where R<1> is SOR<3> and SO2R<3> by reacting a compound with formula (2);

where R<3> is as previously defined, R<7> is an N-protecting group, R<8> is hydrogen, C1-C6 alkyl or OR<9>where R<9> is an O-protecting group and R<10> is hydrogen or bromine, with an oxidizing agent;

b) for the preparation of compounds of formula (1) where

R<1>is SO2R<3>where R<3>is Ci-C6 alkyl, a compound is reduced

with the formula (3):

where R<7> and R<8> are as previously defined and R<10> is hydrogen or bromine, with sodium sulphite, and reacted with a Ci-Ce alkylating agent;

c) for the preparation of compounds of formula (1) where R<1> is SO2NR<4>R<3>, a compound of formula (3) as previously defined, is reacted with an amine: R<4>R<s> NH where R<4> and R<5> are as previously defined;

and then if necessary:

i) the benzazepine ring is debrominated when R<10> is bromine,

ii) one removes an N-protecting group,

iii) alkylate or alkenylate the secondary amino group in the benzazepine ring,

iv) one removes an O protecting group,

v) one alkylates or alkanoylates the hydroxy group in the benzazepine ring,

vi) a pharmaceutically acceptable acid addition salt is formed.

A compound of formula (2) is suitably treated with an oxidizing agent such as hydrogen peroxide or a peracid such as 3-chloroperbenzoic acid in a solvent such as acetic acid. One equivalent of the oxidizing agent gives the sulfinyl compounds and two equivalents gives the sulfonyl compounds.

Conveniently, a compound of formula (3) is treated with sodium sulphite in aqueous sodium bicarbonate and then with a C1-C6 alkylating agent. Suitable alkylating agents are C1-C6 alkyl halides, e.g. Ci-C6 alkyl bromides and iodides, and Ci-Ce dialkyl sulfates.

A compound of formula (3) is suitably reacted with an amine (R<4>R<3>NH) in a solvent such as dichloromethane. When R<4> and R<3> are hydrogen, ammonium hydroxide is preferably used.

In the compounds of formula (2) and (3), the following combinations of substituents are preferred.

R<10> is hydrogen when the groups R<8> and CISO2 or R<3>S are meta or para to each other.

Rio is 9-bromo when R<8> is in the 6-position and CISO2 or R<3>S is in the 7-position.

Rio is 8-bromo when R<8> is in the 7-position and CISO2 or R<3>S is in the 6-position.

R<10> is hydrogen when R<8> is in the 8-position and CISO2 or R3 S is in the 7-position.

The subsequent debromination, N-deprotection, N-alkylation, N-alkenylation, O-deprotection, O-alkylation and O-alkanoylation steps can be carried out by standard methods and can be carried out in different orders of steps to produce the desired connections.

Compounds with formula (2) can be prepared by the following general routes: a) for the preparation of compounds where R<3> is Ci-Ce-alkyl, by treating a compound of formula (4)

where R7 , R<8> and R1° are as previously defined, with a C1-C6 alkylating agent, e.g. a C 1 -C 6 alkyl halide or a C 1 -C 6 dialkyl sulfate;

b) by treating a compound of formula (5):

where R10 is bromine, R11 is R8 and R7 and R8 are as before

defined, with butyllithium and with either (R<3>S)2 or R<3>SCI;

c) for the preparation of compounds where R<8>is OR9 , by treating a compound of formula (5) where R<11>is OH,R<10>

is hydrogen or bromine and R<7> is as previously defined, with R<3> SCI and then protecting the free hydroxyl group;

d) for the preparation of compounds where R<3> is trifluoromethyl, by treating a compound of formula (2) where R<3> is

methyl, with chlorine in the presence of cumene and then with antimony trifluoride and antimony pentachloride.

A compound of formula (4) can be prepared by reducing a compound of formula (3). Appropriately, the reduction is carried out with stannous chloride.

Compounds of formula (3) can be prepared as follows:

a) by treating a compound of formula (5) where R<10> is hydrogen or bromine, R<11> is R8 and R7 and R<8> is as before

defined, with chlorosulfonic acid; and

b) by treating a compound of formula (2) as previously defined with chlorine and aqueous acetic acid.

Suitable N-protecting groups for compounds of formula

(2), (3), (4) and (5) are acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl or benzyloxycarbonyl. Suitable O-protecting groups for compounds of formulas (2), (3), (4)

and (5) is C 1 -C 6 alkyl and benzyl. These groups can be introduced by standard methods.

The compounds of formula (5) can be prepared using methods known in the field, e.g. by brominating a compound of formula (5) where R<10> is hydrogen, or by the methods illustrated in examples 1, 9 and 10 described later.

The compounds of formula (1) form pharmaceutically acceptable acid addition salts with organic or inorganic acids.

Examples of such acids are hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, maleic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid and benzenesulfonic acids.

The salts are formed by methods known in the field. If

the product is isolated as an acid addition salt, it can be treated with an inorganic or organic base such as aqueous sodium hydroxide, sodium carbonate, triethylamine, etc., and transferred into the corresponding free base. The base can then be treated with a corresponding acid, e.g.

in a water-miscible solvent, such as a lower alkanol, preferably methanol or ethanol, and give the desired salt.

The effect of the pharmacologically active compounds produced

in this invention, gastrointestinal motility is demonstrated in the following experimental methods: (1) an increase in the resting pressure of the lower esophageal sphincter (LES) in dogs; and (2) an increase in the rate of gastric emptying in rats.

Procedure for determining LES pressure in anesthetized dogs

Bastard or beagle dogs, male or female, are anesthetized using sodium pentobarbital (35.0 mg/kg, i.v.). Sodium pentobarbital is then continuously infused (approximately 6.0 mg/kg/hour) to maintain deep anesthesia. Blood pressure is controlled through a catheter surgically implanted in the femoral artery and connected to a Gould-Statham P23ID transducer. A catheter is also implanted in the femoral vein to administer the trial drugs. Respiration is maintained by an endotracheal tube attached to a ventilator. A continuously perfused manometric catheter system containing a Dent cuff for measuring sphincter pressure (Dent, Gastroenterology 71: 263-267, 1976) is inserted into the esophagus and positioned so that the intraluminal pressure is recorded from the oesophageal body, the lower esophageal sphincter (LES)

and the blind sac in the stomach. The Dent cuff catheter is perfused with an amount of 0.5 ml of water per my. for each lumen of the catheter using an Arndorfer hydraulic capillary infusion system. A cannula is implanted into the gastric antrum to allow emptying of the perfusate solution and prevent intestinal distension. Continuous development of oesophageal, LES and cecum pressures is checked on a Grass Polygraph (model 7D). Correct placement of the Dent cuff is confirmed by noting a high pressure zone at the LES and by administering an intravenous dose of 5-hydroxytryptamine (normally 10-15 mcg/kg) which contracts the LES but has little or no detectable effect on either the esophageal body or the blind bag. After confirming the placement of the cuff, the animal is allowed to stabilize for approx. 30 minutes.

The compounds are given intravenously, intraduodenal or intra-gastrically. In most cases, subsequent doses of the same or different compounds are given only after the LES pressure has returned to approximately pre-dose baseline values. In all cases, the magnitude of change in LES pressure is determined from the baseline pressure immediately before each treatment to the maximum pressure during treatment. As the compounds used normally have an immediate effect on the LES pressure, no pre-treatment time before measurement is required during this test.

Direct measurement techniques are used to estimate an effective dose 20 (ED20) for the test compound in the individual animals. The mean ED20 and 95% confidence limits are determined using individual ED20 values from a group of animals (N=3) that received the same treatment. ED20 is the dose that increases LES pressure by 20 mm Hg. The ED20's of the 8-hydroxy-7-sulfamoyl and 8-hydroxy-7-methylsulfonyl compounds from Examples 1 and 4 are 50.7 and 27.0 mcg/kg, respectively, i.v.

Gastric emptying in the rat

Fasted rats are given 0.5 [iC± Na 2 3 1 CrO (0.2 ml vol) intragastrically by oral gavage. Connections for evaluation or carrier checks are given either 15 min. before (oral administration) or at the same time as (intravenous administration) the test meal. After 35 min.

the rats are killed by breaking the neck and the stomach is removed. Stomach emptying is measured from the amount of 31 Cr that is back in the stomach at the point of death. In this experiment, the compound from ex. 4 in a dose of

0.5 mg/kg gastric emptying rate compared to the control.

The pharmaceutical compositions for the treatment of stomach and intestinal motility disorders comprise a compound of formula (1) 6-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine or 7-sulfamoyl-2,3,4, 5-tetrahydro-1H-3-benzazepine, or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

The pharmacologically active compounds of formula (1) can be given orally or parenterally. Preferably, these compounds are provided in conventional dosage unit forms prepared by combining an equivalent dose of the compound with standard pharmaceutical carriers. The dosage units will contain the active ingredient in an effective amount selected from approx. 1 mg to approx. 250 mg, preferably 10 mg to 100 mg.

The pharmaceutical carrier used can e.g. be a solid or a liquid. Examples of solid carriers are lactose,

terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrups, peanut oil, olive oil, water and the like.

Similarly, the carrier or diluent may contain a strong time-delaying material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A whole range of pharmaceutical forms can be used. If one

solid carrier is thus used, the preparation can be tableted, placed in a hard gelatin capsule in powder or lump form or in the form of a dragee or lozenge. The amount of solid carrier will vary greatly, but will preferably be from approx. 25 mg to approx. 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or an aqueous or non-aqueous liquid suspension.

The pharmaceutical mixtures are prepared by usual techniques which entail such methods as mixing, granulation and compression if necessary, or varied mixing and dissolution of the components as required to the desired composition.

The method for treating gastrointestinal motility disorders comprises internally administering to a person in need of treatment an effective amount of a compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof.

The compound will preferably be given in a dosage unit form orally or parenterally. Advantageously, equal doses will be given one to four times a day, as the daily dosage range is from approx. 1 mg to approx. 1000 mg, preferably from 10 mg to 400 mg. The method described above is applicable for the treatment of stomach and intestinal motility disorders.

A person skilled in the art will see that in determining the necessary amounts of the compound to produce the desired pharmacological effect without toxic side effects, the activity of the individual compound as well as the size of the host animal must be taken into account.

The following examples illustrate the invention, but are not intended to limit its scope. Temperatures are in °C unless otherwise stated.

Example 1

A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride (50 mL) and N,N-dimethylformamide (6 drops) in toluene (500 mL) was stirred 16 h at 25 °C and concentrated in vacuo to The 3-methoxyphenylacetyl chloride. The acetyl chloride was dissolved in chloroform (100 mL) and added to a solution of aminoacetaldehyde dimethyl acetal (32.1 g, 0.306 m) and triethylamine (32.4 g, 0.320 m)

in chloroform (500 mL) stirred at 5°C. The mixture was stirred at 25°C

for 16 h, washed with water, 1.5N hydrochloric acid and water, dried with magnesium sulfate and concentrated in vacuo to give N-(2,2-dimethoxyethyl)-3-methoxybenzeneacetamide.

A solution of the benzeneacetamide (70 g, 0.277 m) in acetic acid

(180 mL) was added with stirring to concentrated hydrochloric acid (120 mL). The mixture was stirred for 16 hours, diluted with ice/water and filtered. The filter cake was dissolved in methylene chloride which was washed with water, dried with magnesium sulfate and concentrated in vacuo to 2,3-dihydro-8-methoxy-2-oxo-1H-3-benzazepine.

A mixture of 2,3-dihydro-8-methoxy-2-oxo-1H-3-benzazepine

(12 g, 0.063 m) and 10% palladium-on-carbon (1.2 g) in acetic acid (200 mL) were shaken in an atmosphere of hydrogen (4.1 atm), degassed, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride, washed with water, dried with magnesium sulfate and concentrated in vacuo. The residue was triturated with ether and filtered to give 8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine.

A suspension of 8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine (20.4 g, 0.105 m) in tetrahydrofuran (500 mL) was added to 1M borane in tetrahydrofuran (300 ml) stirred at 5°C. The mixture was heated to reflux for 2 hours, cooled, treated with 3N hydrochloric acid (300 mL), concentrated in vacuo to remove tetrahydrofuran and heated to reflux for 1 hour. The mixture was concentrated in vacuo, filtered and the filter cake was dissolved in methanol, heated to reflux, dried with magnesium sulfate and concentrated in vacuo to give 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 229-231°C.

A mixture of 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (4.3 g, 0.02 m) and sodium acetate (3.3 g, 0.04 m) in acetic anhydride (13 mL) was refluxed and stirred for 16 h. concentrated in vacuo and partitioned between methylene chloride and water. The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo to give 3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 89-90°C.

3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

(2.3 g, 0.01 m) was added to chlorosulfonic acid (6 ml) which was stirred at 0°C. The mixture was allowed to warm to 25°C and was stirred for 16 hours. The reaction mixture was then carefully poured into ice water and extracted with methylene chloride. The methylene chloride extracts were combined, washed, dried with magnesium sulfate and concentrated in vacuo to give 3-acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 153-160°C.

3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3 g, 0.007 m) was treated with concentrated ammonium hydroxide (10 mL), stirred for 2 h and filtered , giving 3-acetyl-8-methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 260-263°C.

The sulfonamide (2.3 g, 0.007 m) was slurried in 3N hydrochloric acid and heated under reflux for 16 h. The mixture was concentrated in vacuo and the residue crystallized from methanol to give 8-methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 270-274°C.

8-Methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (1.5 g, 0.005 m) was dissolved in 48% hydrogen bromide (15 mL), refluxed for 2 hours and concentrated in vacuum. The residue was triturated with acetone and then crystallized from methanol to give 8-hydroxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 315-320°C (dec.).

Example 2

3-acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2 g) was stirred with 10 ml of 40% aqueous methylamine, then treated with hydrochloric acid and concentrated in vacuo , giving 8-methoxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This 8-methoxy-7-(N-methylsulfamoyl) compound was treated with boron tribromide in methylene chloride and then with

methanol, giving 8-hydroxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 130-135°C.

Example 3

In the procedure from e.g. 2 and by using dimethylamine instead of methylamine, 8-methoxy-7-(N,N-dimethylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride was obtained which after treatment with boron tribromide gave 8- hydroxy-7-(N,N-dimethylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 195-197°C.

Example 4

Method A

3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (18 g, 0.056 m) was added portionwise to a mixture of sodium sulfite (8.8 g, 0.069 m) and sodium bicarbonate (10.8 g, 0.115 m) in water (36 mL) stirred at 70°C. There was a strong development of gas after the addition. The mixture was stirred for 15 min, treated with iodomethane (8.5 mL, 0.136 m) and refluxed for 45 min. The mixture was partitioned between ethylene chloride and water. The methylene chloride phase was washed with water, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-methoxy-7-methyl-sulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 159-162°C.

Method B

3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (4 g, 0.013 m) was dissolved in glacial acetic acid (80 mL), reacted with stannous chloride dihydrate (11 .6 g, 0.05 m) and concentrated hydrochloric acid (16 ml) and stirred at 75°C for 1 hour. The mixture was cooled,

poured into ice water and extracted with ethyl acetate. The combined ethyl acetate extract was washed, dried with magnesium sulfate and concentrated in vacuo to give a mixture of 3-acetyl-7-mercapto-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine and the corresponding disulfide .

The crude mixture (3 g) was dissolved in ethanol and treated with sodium borohydride (2 g, 0.05 m) to reduce the disulfide of the mercaptan. Methyl iodide (2 g, 0.014 m) was added and the reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated, partitioned between water and methylene chloride, and the combined methylene chloride extract was washed, dried over magnesium sulfate and concentrated in vacuo to give 3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro -1H-3-benzazepine, m.p. 138-140°C.

3-Acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (1.1 g, 0.004 m) dissolved in methylene chloride (10 mL) was treated with 3-chloroperbenzoic acid ( 1.4 g, 0.008 m) and stirred for 1 hour. The mixture was extracted with 5% aqueous sodium carbonate, washed with water, dried with magnesium sulfate and concentrated in vacuo to give 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine , m.p. 162-164°C.

3-Acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1 g, 0.003 m), prepared as in method A or B in 48% hydrogen bromide (15 ml) was heated to reflux for 16 hours and concentrated in vacuo. The residue was triturated with acetone and recrystallized from methanol-water to give 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 300°C (decomposition).

Alternatively, 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine was treated with 3N hydrochloric acid to give 8-methoxy-7-methylsulfonyl-2,3,4,5 -tetrahydro-1H-3-benzazepine hydrochloride, m.p. 228.5-229.5°C. Refluxing this compound with 48% hydrogen bromide gave 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Example 5

By following the general procedure from e.g. 4,

method B, 3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with one equivalent of 3-chloroperbenzoic acid to give 3-acetyl-8-methoxy-7-methylsulfinyl -2,3,4,5-tetrahydro-1H-3-benzazepine. Following the procedure from e.g. 4, 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with 3N hydrochloric acid and gives 8-methoxy-7-methylsulfinyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrochloride. This methoxy compound is treated with pyridine hydrochloride to give 8-hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.

Example 6

A mixture of 8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (1 g, 3.5 mmol), 37% aqueous formaldehyde (1.1 g) and platinum oxide (0.1 g) in ethanol (25 ml) is shaken under an atmosphere of hydrogen (4.1 atm). The mixture is degassed, filtered and concentrated under reduced pressure to give 3-methyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.

By following the procedure from e.g. 4, 3-methyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride is reacted with 48% hydrogen bromide, which gives 8-hydroxy-3-methyl-7-methylsulfonyl -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 310°C (decomposition).

Example 7

3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (12 g, 0.05 mol) essentially prepared as in ex. 4, method B, is dissolved in ethanol-free chloroform (250 ml) containing cumene (10 g) and stirred in the dark. Chlorine is passed through the solution for 48 hours, the mixture is concentrated in vacuo to give 3-acetyl-8-methoxy-7-trichloromethylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.

3-acetyl-8-methoxy-7-trichloromethylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (5.5 g, 0.016 mol), antimony trifluoride (15 g, 0.09

ml) and antimony pentachloride (1.5 g, 0.005 mol) are heated and stirred at 90°C for 24 hours. The resulting mixture is partitioned between chloroform and 3N hydrochloric acid. The chloroform phase is concentrated in vacuo to give 3-acetyl-8-methoxy-7-trifluoromethylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.

By following the procedure from examples 4 method B and 5, 3-acetyl-8-methoxy-7-trifluoromethylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with 3-chloroperbenzoic acid and then hydrolyzed with 3N hydrochloric acid , giving: 8-methoxy-7-trifluoromethylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride and

8-Methoxy-7-trifluoromethylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.

These methoxy compounds are treated with 48% hydrogen bromide to give: 8-hydroxy-7-trifluoromethylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide and

8-hydroxy-7-trifluoromethylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Example 8

A solution of 3-acetyl-7-methoxy-2-3-4-5-tetrahydro-1H-3-benzazepine (2.3 g, 0.01 m) in acetic acid (20 mL) was treated with a solution of bromine (1.8 g, 0.011 m) in acetic acid (10 mL). The mixture was heated to 70°C for 1.5 hours, concentrated in vacuo and partitioned between water and ethyl acetate. The ethyl acetate phase was washed, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. NMR (CDCl 2 ) 6.7, 7.3; aryl protons.

By following the procedure from e.g. 1, 3-acetyl-8-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine is transferred into 3-acetyl-8-bromo-6-chlorosulfonyl-7-methoxy-2,3, 4,5-tetrahydro-1H-3-benzazepine and by the method from ex. 4, this chlorosulfonyl compound is converted into 3-acetyl-8-bromo-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A mixture of 3-acetyl-8-bromo-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (3.7 g, 0.01 m) and 10% palladium- on-carbon (0.37 g) in methanol (50 ml) is stirred in an atmosphere of hydrogen (4.1 atm) until absorption is complete. The mixture is degassed, filtered and concentrated in vacuo to give 3-acetyl-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-benzazepine.

By following the procedure from e.g. 4, 3-acetyl-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with hydrochloric acid to give 7-methoxy-6-methylsulfonyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrochloride which is treated with 48% hydrogen bromide to give 7-hydroxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Example 9

A mixture of 5-bromo-3-hydroxytoluene (93 g, 0.5 m) and sodium hydroxide (21 g, 0.5 m) in water (200 ml) is stirred at 10°C, treated with dimethyl sulfate (63 g, 0 .5 m) for 1 hour, refluxed for 2 hours and cooled. The mixture is diluted with water and extracted with ether. The ether extract is washed, dried with sodium sulfate and concentrated in vacuo to give 5-bromo-3-methoxytoluene.

A mixture of 5-bromo-3-methoxytoluene (20 g, 0.1 m), N-bromosuccinimide (17.8 g, 0.1 mL) and dibenzoyl peroxide in carbon tetrachloride (200 mL) is heated to reflux and irradiated with a solar lamp. The mixture is cooled, filtered and concentrated in vacuo to give 5-bromo-3-methoxybenzyl bromide.

A mixture of the crude benzyl bromide and sodium cyanide (4.9 g, 0.1 m) in ethanol (500 ml) is stirred at 65°C for 16 hours. The mixture is cooled, filtered and concentrated in vacuo. The residue is distributed between water and chloroform and the chloroform phase is washed, dried with sodium sulfate and concentrated in vacuo, which gives 5-bromo-3-methoxyphenylacetonitrile.

A mixture of 5-bromo-3-methoxyphenylacetonitrile (22.6 g,

0.1 m) and 10% aqueous sodium hydroxide (300 ml) in ethanol (225 ml) are heated to 95°C for 18 hours. The mixture is concentrated in vacuo, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed, dried with sodium sulfate and concentrated in vacuo to give 5-bromo-3-methoxyphenylacetic acid.

By following the general procedure from e.g. 1, 5-bromo-3-methoxyphenylacetic acid is transferred into a mixture of 6-bromo-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine and 8-bromo-6-methoxy-2,3, 4,5-tetrahydro-1H-3-benzazepine. The isomers are separated by preparation

HPLC.

Each isomer (2.6 g, 0.01 m) is dissolved in 98% formic acid (50 mL) and 37% aqueous formaldehyde (10 mL), then heated to 95°C for 5 h, poured into ice water, basified with 10 % aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract is washed, dried with sodium sulfate and concentrated in vacuo, yielding separately 6-bromo-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 8-bromo-6- methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution of 6-bromo-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.7 g, 0.01 m) in toluene (30 mL) is added to a solution of n-butyllithium (0.044 m) in toluene (15 mL) stirred at -78°C. The mixture is stirred for 30 min., treated with a solution of methyl disulfide (8.2 g, 0.087 m) in toluene (10 ml), stirred for 15 min.

and poured into water (125 ml). The mixture is acidified with 10% hydrochloric acid, and the aqueous phase is washed with ether, made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract is washed, dried with sodium sulfate and concentrated in vacuo to give 8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.

By following the procedure from e.g. 4, method B, 8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is transferred into 8-methoxy-3-methyl-6-methylsulfonyl-2,3, 4,5-tetrahydro-1H-3-benzazepine hydrochloride, which is treated with hydrogen bromide to give 8-hydroxy-3-methyl-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

By the same procedure, 8-bromo-6-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is transferred into 6-methoxy-3-methyl-8-methylsulfonyl-1H-3-benzazepine -hydrochloride, which is treated with 48% hydrogen bromide to give 6-hydroxy-3-methyl-8-methylsulfonyl-1H-3-benzazepine hydrobromide.

Example 10

A mixture of 2,3-dimethylanisole (2 g, 0.014 m), N-bromosuccinimide (5.3 g, 0.03 m) and dibenzoyl peroxide (8 mg) in carbon tetrachloride (50 mL) was heated to reflux and irradiated with a solar lamp for 45 min. The mixture was cooled, filtered and concentrated in vacuo to give 2,3-bis(bromomethyl)anisole which was triturated with methanol (m.p. 70°C).

A solution of 2,3-bis(bromomethyl)anisole (43 g, 0.146 m) in dimethyl sulfoxide (150 mL) was added to a stirred mixture of sodium cyanide (28.7 g, 0.585 m) and dimethyl sulfoxide (200 mL) . The mixture was cooled so that the internal temperature did not exceed 60°C during the addition of the dibromide. The mixture was stirred for 1 hour at 50°C, then poured into ice water and filtered to give 3-methoxy-1,2-phenylene-diacetonitrile.

A mixture of 3-methoxy-1,2-phenylenediacetonitrile (44 g,

0.236 m) and Raney nickel in ethanol saturated with ammonia was heated to 100°C in a hydrogen atmosphere (75 atm) for 2 hours. The mixture was cooled, degassed, filtered, concentrated in vacuo and partitioned between 10% aqueous hydrochloric acid and ethyl acetate ether (1:1).

The aqueous phase was basified with 40% aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with magnesium sulfate and concentrated in vacuo. The residue was treated with maleic acid and crystallized from acetonitrile to give 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine maleate, m.p. 153-155°C.

By following the procedure from examples 1 and 4, 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine is transferred through 3-acetyl-6-methoxy-9-methylsulfonyl-2,3,4,5- tetrahydro-1H-3-benzazepine to 6-methoxy-9-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, which is treated with hydrogen bromide to give 6-hydroxy-9-methylsulfonyl-2, 3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Example 11

By following the procedure from examples 1 and 8, 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine is transferred through 3-acetyl-6-methoxy-7-methylenesulfonyl-9-bromo-2,3, 4,5-tetrahydro-1H-3-benzazepine in 6-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, which is treated with hydrogen bromide to give 6-hydroxy-7- methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Example 12

A mixture of 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.2 g, 0.01 m) in trifluoroacetic acid

(25 ml) is stirred at 25°C and treated with acetyl bromide (1.4 g,

0.011 m). The mixture is stirred at 25°C and concentrated in vacuo to give 8-acetoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Example 13

8-Hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide is treated with 1 equivalent of sodium hydroxide in aqueous solution. Extraction in chloroform and evaporation gives 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

Example 14

Allyl bromide is added to a mixture of 8-hydroxy-7-methyl-sulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1 equivalent) in acetone containing potassium carbonate, and the mixture is stirred at 5°C, then at 25°C and finally at reflux. The mixture is then poured into water, extracted with ethyl acetate and treated with hydrogen in ether to give 3-allyl-8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.

Example 15

By following the procedure from examples 1 and 4, 2,3,4,5-tetrahydro-1H-3-benzazepine is transferred into 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and then in 3-acetyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine which is hydrolyzed with hydrochloric acid to 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine- hydrochloride, m.p. 275-277°C.

Example 16

By following the procedure from examples 4 and 5, 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is transferred into 3-acetyl-7-methylthio-2,3,4,5- tetrahydro-1H-3-benzazepine and then into 3-acetyl-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine,

which is hydrolysed with dilute hydrochloric acid to give 7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.

Example 17

Following the procedure of Examples 1, 15 and 16, 3-methylphenylacetic acid is transferred into 3-acetyl-7-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and then into 3-acetyl-8-methyl -7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine which is transferred into 8-methyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride or 8 -methyl-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.

Example 18

With the procedure from e.g. 4, method B using propyl iodide instead of methyl iodide, 3-acetyl-8-methoxy-7-propylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is obtained, which after treatment with hydrogen bromide gives 8-hydroxy- 7-propylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 177-180°C.

Example 19

8-Hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (10 g) is mixed with 75 mg of lactose and 2 mg of magnesium stearate. The resulting mixture is filled into a hard gelatin capsule.

Claims (6)

1. Method for producing a compound of formula (1): where R is hydrogen or C 1 -C 6 alkyl or C 1 -C 8 alkenyl; R<1> is SOR 3 , SO 2 R 3 or SO 2 NR 4 R 3 ; R<2> is hydrogen, C1-C6 alkyl or R<6>O-; R<3> is C1-C6 alkyl or trifluoromethyl; R4 and R<3> are hydrogen or C1-C6 alkyl; and R<6>is hydrogen, C1-C6-alkyl or C1-C6-alkanoyl, provided that when R<1>is SO2NH2, R<2>R<6>0- or C1-C6-alkyl, or a pharmaceutically acceptable acid addition salt thereof, characterized in that one a) for the preparation of compounds of formula (1) where R<1> is SOR<3> and SO2R<3> reacts a compound of formula (2): where R<3> is as previously defined, R<7> is an N-protecting group, R<8> is hydrogen, C1-C6 alkyl or OR<9>where R<9> is an O-protecting group and R<10> is hydrogen or bromine, with an oxidizing agent; b) for the preparation of compounds of formula (1) where R<1>is SO2R<3>where R<3>is Ci-C6-alkyl, reduces a compound of formula (3): where R<7> and R<8> are as previously defined and R<10> is hydrogen or bromine, with sodium sulfite and reacting with a Ci-Ce alkylating agent; c) for the preparation of compounds where R<1>is SO2 NR4 R3 , reacts a compound of formula (3) as previously defined with an amine : R<4>R<3>NH where R<4> and R<3> are as previously defined; and then if necessary: i) debrominate the benzazepine ring when R<10> is bromo, ii) remove an N-protecting group, iii) alkylate or alkenylate the secondary amino group in the benzazepine ring, iv) remove an O-protecting group, v) alkylate or alkanoylates the hydroxy group in the benzazepine ring, vi) forms a pharmaceutically acceptable acid addition salt. 2. Method according to claim 1 in the preparation of a compound of formula (1) where R<2> is in the 8-position, characterized by using correspondingly substituted starting materials. 3. Process according to claim 1 for the preparation of compounds with formula (1) where R<2> is in the 8-position and R<1> is in the 7-position, characterized by using correspondingly substituted starting materials. 4. Process according to claim 1 for the preparation of compounds with formula (1) where R<1> is SO2R<3> or SO2NR<4>R<3>, R<2> is hydrogen, C1-C6 alkoxy or hydroxy, R<3> is methyl and R is hydrogen, characterized by using correspondingly substituted starting materials. 5. Process according to claim 1 in the preparation of: 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-hydroxy-7-(methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-hydroxy-7-(N,N-dimethylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; or 8-hydroxy-7-propylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or a pharmaceutically acceptable acid addition salt thereof, characterized by using correspondingly substituted starting materials. 6. Process for the preparation of a pharmaceutical mixture, characterized in that one brings together a compound of formula (1) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.